Effector T cells in rheumatoid arthritis: Lessons from animal models

Alzabin, Saba; Williams, Richard O.

doi:10.1016/j.febslet.2011.04.034

Cited by 71 publications

(65 citation statements)

References 177 publications

(247 reference statements)

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“…MHC class II molecules present antigens to CD4+ T cells and these cells are present in the synovium of inflamed joints in both humans and animals (Alzabin and Williams, 2011;Todd et al, 1988). The requirement for CD4+ T cells in the initiation of arthritis has been demonstrated in CIA by anti-CD4 mAb treatment prior to onset, however it does not ameliorate established disease (Williams and Whyte, 1996), a result reflected in human clinical trials (Keystone, 2002).…”

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confidence: 99%

Animal models of rheumatoid arthritis: How informative are they?

McNamee

Williams

Seed

2015

European Journal of Pharmacology

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Animal models of arthritis are widely used to de-convolute disease pathways and to identify novel drug targets and therapeutic approaches. However, the high attrition rates of drugs in Phase II/III rates means that a relatively small number of drugs reach the market, despite showing efficacy in pre-clinical models. There is also increasing awareness of the ethical issues surrounding the use of animal models of disease and it is timely, therefore, to review the relevance and translatability of animal models of arthritis. In this paper we review the most commonly used animal models in terms of their pathological similarities to human rheumatoid arthritis as well as their response to drug therapy. In general, the ability of animal models to predict efficacy of biologics in man has been good. However, the predictive power of animal models for small molecules has been variable, probably because of differences in the levels of target knockdown achievable in vivo.3

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confidence: 99%

Animal models of rheumatoid arthritis: How informative are they?

McNamee

Williams

Seed

2015

European Journal of Pharmacology

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“…RA has been regarded as a classic T cell-mediated chronic inflammatory autoimmune disease for years. Abnormal activation of T cells in RA are the main induced factors causing immune damage and synovial pathologic histology change (Alzabin and Williams, 2011;Rodeghero et al, 2013). In our previous study, we found that CK alleviated CIA and adjuvant-induced arthritis, downregulated the percentage of activated T cells, and upregulated naive T cells and regulatory T cells (Tregs) in spleen Liu et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Ginsenoside Metabolite Compound K Suppresses T-Cell Priming via Modulation of Dendritic Cell Trafficking and Costimulatory Signals, Resulting in Alleviation of Collagen-Induced Arthritis

Chen

Wang

et al. 2015

J Pharmacol Exp Ther

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Ginsenoside metabolite compound K (CK; 20-O-D-glucopyranosyl-20(S)-protopanaxadiol), a novel ginsenoside metabolite, belongs to the dammarane-type triterpene saponins, according to its structure. The anti-inflammatory activity of CK has been identified in several studies. Our study demonstrated that CK exerted an anti-inflammatory effect in collagen-induced arthritis (CIA) and adjuvant-induced arthritis animal models, and this effect was due to inhibition of the abnormal activation and differentiation of T cells. However, the mechanism of CK in suppressing T-cell activation remains unclear. In this study, CK had a therapeutic effect in mice with CIA, decreased the percentage of activated T cells and dendritic cells (DCs), and increased the percentage of naive T cells in lymph nodes. The inhibitory effect on T-cell activation of CK was related to suppression of accumulation of DCs in lymph nodes. CK decreased CCL21 levels in lymph nodes and CCR7 expression in DCs and suppressed CCL21/CCR7-mediated migration of DCs, thus reducing accumulation of DCs in lymph nodes. In addition, signals for T-cell activation including major histocompatibility complex class II and costimulatory molecules, such as CD80 and CD86, were suppressed by CK, and the proliferation of T cells induced by DCs was inhibited by CK. In conclusion, this study demonstrated that CK downregulated DC priming of T-cell activation in CIA, and suppression of CCL21/CCR7-mediated DC migration and signaling between T cells and DCs might be the potential mechanism. These results provide an interesting, novel insight into the potential mechanism by which CK contributes to the anti-inflammatory effect in autoimmune conditions.

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“…The microenvironment of an inflamed RA joint is characterized by though RA is likely a T cell dependent disease, no arthritogenic T cell population has been identified yet. The key role of T cells in pathogenesis of RA can be illustrated by the fact that depletion of CD4 + T cells in murine experimental models alleviated the disease severity and autoantibody production [17][18][19]. However, no apparent clinical resolution was seen after depletion of CD4 + T cells in the clinical trials on RA patients [20].…”

Section: Pathogenesis Of Ramentioning

confidence: 99%

Systemic and local regulation of experimental arthritis by IFN-α, dendritic cells and uridine

Narendra¹

2017

Linköping University Medical Dissertations

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In this thesis, we have studied the immunological processes of joint inflammation that may be targets for future treatment of patients with arthritis. We focus on the immune-modulating properties of interferon-α (IFN-α) and uridine in experimental arthritis. The nucleoside uridine, which is regarded a safe treatment has anti-inflammatory properties notably by inhibiting tumor necrosis factor (TNF) release. Because the inflamed synovium in rheumatoid arthritis (RA) is characterised by pathogenic TNF-production, uridine could potentially be away to ameliorate arthritis. Systemic administration of uridine had no effect on antigeninduced arthritis (AIA), which is a T-cell dependent model where animals are immunized twice (sensitization) with bovine serum albumin (mBSA), before local triggering of arthritis by intra-articular antigen (mBSA) re-challenge. In contrast, intra-articular administration of uridine clearly down modulated development of AIA in a dose dependent manner and inhibited the expression of synovial adhesion molecules, influx of inflammatory leukocytes and synovial expression of TNF and interleukin 6, but did not affect systemic levels of proinflammatory cytokines or antigen-specific T-cell responses. Local administration of uridine may thus be a viable therapeutic option for treatment of arthritis in the future. Viral double-stranded deoxyribonucleic acid (dsRNA), a common nucleic acid found in most viruses, can be found in the joints of RA patients and local deposition of such viral dsRNA induces arthritis by activating IFN-α. Here we show that arthritis induced by dsRNA can be mediated by IFN-producing dendritic cells in the joint and this may thus explain why viral infections are sometimes associated with arthritis. Earlier, to study the effect of dsRNA and IFN-α in an arthritis model, that like RA, is dependent on adaptive immunity, dsRNA and IFN-α were administered individually during the development of AIA. Both molecules clearly protected against AIA in a type I IFN receptor-dependent manner but were only effective if administered in the sensitization phase of AIA. Here we show that the anti-inflammatory effect of IFN-α is critically dependent on signalling via transforming growth factor β (TGF-β) and the enzymatic activity of indoleamine 2,3 dioxygenase 1 (IDO). The IDO enzyme is produced by plasmacytoid DC and this cell type was critically required both during antigen sensitization and in the arthritis phase of AIA for the protective effect of IFN-α against AIA. In contrast, TGF-β and the enzymatic activity of IDO were only required during sensitization, which indicate that they are involved in initial steps of tolerogenic antigen sensitization. In this scenario, IFN- α first activates the enzymatic activity of IDO in pDC, which converts Tryptophan to Kynurenine, which thereafter activates TGF-β. Common for IDO-expressing pDC, Kyn and TGF-β is their ability to induce development of regulatory T cells (Tregs). We found that Tregs were crucial for IFN-α-mediated protection against AIA, but onl...

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Effector T cells in rheumatoid arthritis: Lessons from animal models

Cited by 71 publications

References 177 publications

Animal models of rheumatoid arthritis: How informative are they?

Animal models of rheumatoid arthritis: How informative are they?

Ginsenoside Metabolite Compound K Suppresses T-Cell Priming via Modulation of Dendritic Cell Trafficking and Costimulatory Signals, Resulting in Alleviation of Collagen-Induced Arthritis

Systemic and local regulation of experimental arthritis by IFN-α, dendritic cells and uridine

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